Treating a patient with a pharmaceutically active substance is commonly performed by periodically administering a defined dose of the pharmaceutical either orally (enteral) or by inJection (parenteral). In order to assure that an effective dosage of the drug is present in the patient's body at all times, peak dosages that are much higher than the effective level usually need to be initially administered. Such a procedure undesirably increases the amount of the drug that is consumed and also increases the danger of undesirable side effects. In addition, even when a substantially excessive dosage is initially administered, there is a danger that the pharmaceutical's concentration may drop below its effective level if a subsequent dosage is delayed or omitted.
Another technique that is commonly used for administering a pharmaceutical to a patient is through intravenous infusion. While this technique generally works well in providing a sustained effective level of the pharmaceutical, it is cumbersome and typically requires close supervision by trained medical personnel. Consequently, intravenous infusion generally requires the patient to be hospitalized with the associated expense and inconvenience.
Techniques and devices have also been developed for administering pharmaceuticals at therapeutic levels and rates by absorption through a patient's skin. Such delivery devices, which are now commercially available for nitroglycerin and other pharmaceuticals and include transdermal or transmucosal patches or bandages, implants, osmotic devices and the like, are very useful in continuously administering a medication at a relatively constant rate. These devices typically include a pharmaceutical-containing reservoir enclosed by a membrane through which the drug diffuses at a controlled rate. The device is typically attached either adhesively or mechanically to the patient's skin, and the drug diffuses from the device and permeates the outer sublayers of the patient's skin until it is absorbed into the bloodstream of the dermis capillary network. Once the drug enters the bloodstream, it is carried throughout the patient's entire body.
While such transdermal delivery devices work well for some pharmaceuticals such as nitroglycerine, conventional transdermal delivery devices have not proved to be suitable for many other important drugs. Specifically, the absorption rate or flux through skin for some pharmaceuticals from conventional devices has been found to be too slow to provide an effective dosage unless the size of the transdermal patch is excessively large. For example, in the case of large molecular weight drugs such as buprenorphine, which is a lipophilic opioid analgesic (see U.S. Pat. No. 3,433,791, which is incorporated herein by reference), it has been found that the drug will not readily permeate a patient's skin at a therapeutic rate if a reasonably-sized patch is used unless the skin is "softened" by using a skin permeation enhancing agent. More specifically, it has been found that the skin permeation rate for large molecular weight drugs such as buprenorphine can be significantly increased if the drug is mixed with a permeation enhancing agent such as a polar solvent material selected from the group consisting of C.sub.3 -C.sub.4 diols, C.sub.3 -C.sub.6 triols, and mixtures thereof; and/or a polar lipid material selected from the group consisting of fatty acids, fatty alcohols, fatty alcohol esters, fatty acid esters, and mixtures thereof. Even more specifically, it has been found that the skin permeation rate for large molecular weight drugs such as buprenorphine can be significantly raised if the drug is mixed with a permeation enhancing agent such as propylene glycol, which is basically a polar C.sub.3 diol; and/or methyl laurate and methyl caprylate, which are basically lipophilic fatty acid esters.
Many previous transdermal drug delivery devices such as those disclosed in U.S. Pat. Nos. 4,564,010 to Coughlan et al. and 4,262,003 to Urquhart et al. are constructed from common packaging materials such as polyethylene and polypropylene, which are relatively inexpensive, easy to handle, and easy to seal. It has been found that such packaging material can be used to contain a diol-based skin permeation enhancer such as propylene glycol with relative ease. However, significant problems result when these same materials are used to contain a lipid component such as methyl laurate or methyl caprylate, which in some instances may be present in amounts ranging from about 1% to about 40% by weight of the total drug formulation. Specifically, hydrophobic polymers such as common polyolefins tend to readily absorb lipophilic solvents from the diol. Accordingly, depending on the drug/skin permeation enhancer formulation, the loss of the lipophilic solvent can significantly decrease the drug's solubility in the formulation and thereby cause the drug to precipitate out while the patch is in storage or during use. In addition, the solvent's loss can significantly reduce the drug flux or absorption rate through the patient's skin. Finally, the solvent entering the packaging material can significantly alter the material's physical properties which can catastrophically impact the integrity of the overall patch structure.
Additional research has shown that common environmental factors such as the presence of moisture, oxygen, and light can adversely affect the stability and efficacy of some drugs and skin permeation enhancers, which in turn can significantly impact the storage stability or shelf life of the transdermal device. For example, it has been found that the solubility of buprenorphine and the lipophilic solvents in some skin permeation enhancers such as propylene glycol decreases significantly if the formulation absorbs even a very small fraction of water. It is also been found that some drugs such as buprenorphine can degrade when exposed to light. Most prior drug delivery device architectures do not specifically address the objective of protecting the drug formulation from common environmental factors.
Most prior transdermal drug delivery devices use a dermatologically-acceptable, pressure-sensitive adhesive to secure the device to a patient's skin. In many of these structures, the drug formulation is allowed to freely come into contact with the adhesive examples of which include U.S. Pat. Nos. 3,742,951 to Zaffaroni; 4,144,317 to Higuchi et al.; 4,262,003 to Urquhart et al.; 4,690,683 to Chien et al.; and 4,764,379 to Sanders et al. However, it has been found that many of these adhesives might absorb some skin permeation enhancing agents such as propylene glycol. In addition, it has been found that lipophilic solvents such as methyl laurate and methyl caprylate will swell and even dissolve many adhesives, particularly silicones, polyisobutylenes, and acrylic-based adhesives. Accordingly, many prior transdermal devices are not suitable for containing some types of drug/skin permeation enhancer formulations.
In light of the above, the principal object of the present invention is to provide a transdermal drug delivery system that will uniformly administer a pharmaceutical to a patient in need of such treatment.
Another principal object of the present invention is to construct a transdermal drug delivery device that includes various barrier materials that will not significantly absorb the pharmaceutical and/or a skin permeation enhancer contained therewithin thereby significantly increasing the device's stability and shelf-life.
A further object of the present invention is to construct a transdermal drug delivery device that is made from barrier materials that will significantly increase the shelf life of the device by protecting the drug and/or skin permeation enhancer from common environmental factors such as moisture, oxygen, and light.
Another object of the present invention is to construct a transdermal drug delivery device such that the drug formulation is not exposed to the adhesive used to maintain the device on a patient's skin.